Comparison of clinicopathological characteristic for different etiological subtypes in ICC Patients
A total of 448 patients undergoing radical resection for histologically confirmed ICC between 2010 and 2018 were considered for inclusion. The comparison of clinicopathological characteristic of Con-ICC (no identifiable cause, n=261, 58.2%), HBV-ICC (n=102, 22.8%) and Stone-ICC (n=85, 19.0%) was summarized in Table 1. The three etiological subtypes in ICC patients had a certain correlation with clinicopathological characteristics of sex, age (year), obstructive jaundice, CA19-9, Child-Pugh grade, tumor location, morphologic grape, perineural invasion, liver capsule involvement, and AJCC 8th edition N stage (P<0.05). In addition, Stone-ICC had a higher proportion of CA19-9 >39.0 U/ml, presence of perineural invasion, and morphologic grape with periductal infiltrating and intraductal growth compared with HBV-ICC (P<0.05).
Survival analysis on OS and RFS in the whole cohort
The 1-, 3-, and 5-year OS rates of ICC patients were 84.9%, 42.4%, and 20.0%, and 1-, 3-, and 5-year RFS rates of ICC patients were 56.5%, 20.6%, and 10.3%, respectively. Median OS and RFS were 28.0 and 14.9 months, respectively. Univariate analysis showed that different etiology was a prognostic factor for OS and RFS of patients with ICC after radical resection, respectively (Supplement Fig 1, P<0.05). Multivariate analysis showed that different etiology was an independent risk factor for OS. Detailed results of the univariate and multivariate analysis are shown in Table 2.
To eliminate the differences and be comparable of baseline clinicopathological characteristics between related two subtypes, a 1:1 PSM was utilized to identify 102 pairs of patients with Con-ICC and HBV-ICC, 70 pairs of patients with Con-ICC and Stone-ICC, 37 pairs of patients with HBV-ICC and Stone-ICC. Before and after PSM, the OS and RFS of patients with Con-ICC and HBV-ICC were not statistically significant (Fig 1, 2-A and B, P>0.05); however, the OS of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (Fig 1, 2-C and E, P<0.05), while the RFS of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (Fig 2- D and F, P>0.05). Therefore, the results showed that the prognosis of Stone-ICC subtype was significantly worse than those of Con-ICC and HBV-ICC subtypes.
Comparison of recurrence and survival
By comparing overall recurrence, early recurrence (RFS≤1 year after surgery, ), and OS for the different etiological subtypes in a proportion of ICC patients, the results showed that there was no statistical difference in the proportion of patients with overall recurrence and early recurrence (Fig 3-A and B, P>0.05). By further comparing the difference of OS≤1 year, OS with 1~3 year and OS >3 years in early recurrence patients, there was a statistical difference with the three etiological subtypes, and Stone-ICC tended to have a worse prognosis (Fig 3-C, P<0.05), while there was no statistical difference in non-early recurrence patients (Fig 3-D, P>0.05). Therefore, the survival difference of the three etiological subtypes was mainly for OS in patients with early recurrence.
Comparison of OS and RFS in ACT
To determine whether the ACT regimens affected the prognosis of patients, we first analyzed the prognosis differences among the four regimens for patients with postoperative ACT, and the results showed that there was no difference in OS and RFS among different chemotherapy regimens (P > 0.05). By analyzing the prognostic improvement value of ACT for different etiological subtypes in ICC patients, the results showed that in Con-ICC patients, the median OS was 30.2 months and 30.2 months, and the median RFS was 14.9 months and 19.0 months for non-ACT and ACT patients, respectively (Fig 4-A and B, P > 0.05); in HBV-ICC patients, the median OS was 38.0 months and 44.5 months, and the median RFS was 13.0 months and 15.3 months for non-ACT and ACT patients, respectively (Fig 4-C and D, P > 0.05); in Stone-ICC patients, the median OS was 16.0 months and 29.7 months, and the median RFS was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (Fig 4-E and F, P < 0.05). Therefore, postoperative ACT can improve the OS and RFS of Stone-ICC patients effectively.